pLM4CPPs: Protein Language Model-Based Predictor for Cell Penetrating Peptides

Cell-penetrating peptides (CPPs) are short peptides capable of penetrating cell membranes, making them valuable for drug delivery and intracellular targeting. Accurate prediction of CPPs can streamline experimental validation in the lab. This study aims to assess pretrained protein language models (pLMs) for their effectiveness in representing CPPs and develop a reliable model for CPP classification. We evaluated peptide embeddings generated from BEPLER, CPCProt, SeqVec, various ESM variants (ESM, ESM-2 with expanded feature set, ESM-1b, and ESM-1v), ProtT5-XL UniRef50, ProtT5-XL BFD, and ProtBERT. We developed pLM4CCPs, a novel deep learning architecture using convolutional neural networks (CNNs) as the classifier for binary classification of CPPs. pLM4CCPs demonstrated superior performance over existing state-of-the-art CPP prediction models, achieving improvements in accuracy (ACC) by 4.9-5.5%, Matthews correlation coefficient (MCC) by 9.3-10.2%, and sensitivity (Sn) by 14.1-19.6%. Among all the tested models, ESM-1280 and ProtT5-XL BFD demonstrated the highest overall performance on the kelm data set. ESM-1280 achieved an ACC of 0.896, an MCC of 0.796, a Sn of 0.844, and a specificity (Sp) of 0.978. ProtT5-XL BFD exhibited superior performance with an ACC of 0.901, an MCC of 0.802, an Sn of 0.885, and an Sp of 0.917. pLM4CCPs combine predictions from multiple models to provide a consensus on whether a given peptide sequence is classified as a CPP or non-CPP. This approach will enhance prediction reliability by leveraging the strengths of each individual model. A user-friendly web server for bioactivity predictions, along with data sets, is available at https://ry2acnp6ep.us-east-1.awsapprunner.com. The source code and protocol for adapting pLM4CPPs can be accessed on GitHub at https://github.com/drkumarnandan/pLM4CPPs. This platform aims to advance CPP prediction and peptide functionality modeling, aiding researchers in exploring peptide functionality effectively.